OVERALL PROJECT SUMMARY The overarching goal of this SPORE renewal proposal is to devise and test novel forms of cellular immunotherapy mediated by T cells and NKT cells to treat non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). A distinguished cadre of molecular biologists, immunologists and clinical investigators with exemplary histories of productive translational research, and supported by four shared core resources, has been recruited for this effort. To address the persistent challenges of unsustained complete remissions and unacceptable rates of treatment-related toxicity, investigators in this program have proposed four distinct lines of research, each involving an early-phase clinical trial. 1) Use highly specific T and natural killer T (NKT) cell immunotherapies to target multiple lymphoma antigens. This objective will be pursued in each project using either native or chimeric antigen receptors (CARs) or both. 2) To increase the potency of the T and NKT cell immunotherapies for lymphoma. This will entail an immunomodulatory agent, 5-azacytidine, to increase tumor antigen expression (Project 1); developing CARs for independent targets on T cell lymphoma (Project 2); adding a nonlytic costimulatory CAR to supply increased ?signal-2? elements to improve the expession and perisistence of EBV-specific T cells (Project 3); and use of a CD19-CAR to enhance tumor recognition and provide added costimulation (Project 4). 3) Overcome the immune evasion tactics of lymphoma cells and their microenvironment. Investigators will use a modified inverted cytokine receptor to interact with immunosuppressive molecules at the tumor site while delivering positive costimulatory signals (Project 1); will exploit a novel costimulatory CAR to enable T cells to sustain their activation in the presence of immunosuppressive molecules (Project 3); and will take advantage of the ability of NKT cells to overcome the immunosuppressive microenviornment to boost response rates (Project 4). 4) Make T and NKT cell immunotherapy more broadly applicable. Innovations in the manufacturing practices of this SPORE will continue to improve the technologies required for the success of each project, including further reductions in the length and complexity of T-cell preparation (Projects 1-3) and use of banked NKT cells as an ?off-the- shelf? product (Project 4). At the conclusion of these proposed studies, we will have evaluated the clinical feasibility and safety of several novel immunotherapy approaches to NHL and HL, and gained valuable insight into the immune variables that correlate with clinical outcome after targeted immunotherapy. These achievements will represent substantive steps toward the development of novel lymphoma treatments that are both potent and widely accessible.